Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis

Acute kidney injury secondary to VAN therapy is a well-characterized adverse effect, while AKI incidence secondary to PTZ is less understood. Additionally, there appears to be an additive effect when these agents are used in combination. This is the largest review of AKI in patients receiving VAN,PTZ, or the combination of both agents.

There is increasing evidence suggesting greater nephrotoxicity in patients treated with the combination of VAN and antipseudomonal beta-lactams. The mechanism for the apparent increase in nephrotoxicity with this drug combination is not well understood and needs further study in both animal models and humans.

Acute kidney injury rates related to VAN vary widely, with recent studies in critically ill and internal medicine patients estimated at 21% and 13.6%, respectively.^2,3 In our VAN monotherapy cohort, the AKI rate was 8.3%, with 2.3% of patients experiencing a greater than 50% decrease in creatinine clearance. Piperacillin-tazobactam-related AKI rates are not well characterized; however, a small retrospective analysis estimated that 11.1% of PTZ patients experienced acute renal failure (defined as either increase in serum creatinine greater than 0.5 mg/dL or 50% increase from baseline).¹³ In the present study, we found the PTZ-related AKI rate to be 7.8%, which may be due to a more stringent definition of AKI. Additionally, Hellwig et al¹³ found that PTZ monotherapy was associated with higher AKI rates compared to VAN monotherapy (11.1% vs 4.9%; P = 0.014). This was not replicated in our study, with VAN and PTZ monotherapy having similar AKI rates (8.3% and 7.8%, respectively) and an adjusted aOR of 0.88 (95% CI 0.0.73-1.08) for AKI in PTZ- compared to VAN-treated patients. The estimated AKI incidence of 21% in the combination therapy group at our institution is consistent with literature that ranges from 16.3% to 34.8%.^4-8,13

To control for differences in baseline severity of illness, we performed a subgroup analysis of patients with similar CCI scores. The finding of increased AKI in patients receiving combination VAN and PTZ was consistent in each subgroup, suggesting that the increase in AKI is independent of illness severity.

This study is not without limitations. As with all retrospective studies, it is difficult to determine a causal link between VAN and PTZ combination therapy and increased AKI incidence due to confounding. We employed a rigorous study design that controlled for major confounders of AKI, such as concomitant nephrotoxic exposure, hypotension, and renal disease. Severity of illness was measured with CCI, which may not accurately capture the severity of illness at treatment initiation. Alternatives, such as acute physiology and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores, may more accurately reflect critical illness on presentation; however, this study was not focused specifically on critically ill patients. In addition to baseline comorbidity, we controlled for hypotension and dehydration as a surrogate marker for critical illness. In the subgroup analysis of patients with similar CCI, the effect of VAN/PTZ on AKI compared to VAN or PTZ monotherapy was consistent in each group. Nephrotoxic potential of agents was assumed to be equal, which is not necessarily true. Additionally, the binary representation of nephrotoxic exposure does not describe the amount of the agent received; as such, our estimations of AKI odds may be artificially elevated. Approximately one-quarter of the patients in this study were transferred from an outside hospital, for which no data regarding initial treatment are available. This may lead to exposure misclassification. We attempted to control for this factor in the regression model and found that, after controlling for other covariates, hospital transfer was associated with increasing odds of AKI. Finally, data were collected retrospectively from the electronic medical record and are subject to inaccuracies documented in the chart; however, any bias introduced should be nondifferential.

In our large retrospective study of combination empiric therapy with VAN and PTZ, we found that combination therapy was associated with more than double the odds of AKI occurring compared to either monotherapy with VAN or PTZ. Increasing duration of therapy was also associated with increases in AKI. These findings demonstrate the need for judicious use of combination therapy and strengthen the need for antimicrobial de-escalation when appropriate to avoid deleterious effects.

Acknowledgments

The authors thank Chantal Le Rutter, MPA, for copyediting services.

Disclosures

This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant numbers UL1TR000117 and UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.